Vaccine trials in non-human primates challenged with R5, tier 2 SHIVs have shown protection in the presence of high levels of non-neutralizing antibodies (NNAbs), and one of the 5 Phase IIb HIV-1 vaccine efficacy trials using alum (ALVAC/AIDSVAX in RV144) showed an estimated vaccine efficacy of 31%, with a correlate of decreased transmission risk of V2 and other FcR-mediated anti-HIV antibodies. NNAbs are polyfunctional antibodies capable of mediating a number of FcR-mediated or complement-mediated functions such as ADCC, antibody dependent cellular phagocytosis (ADCP) or NK cytokine production. A new efficacy trial is ongoing to follow-up on RV144, called HVTN702, using ALVAC-C, a bivalent clade C gp120 boost, and the adjuvant MF59. We have demonstrated that a multivalent wildtype (WT) Env ALVAC/protein vaccine protected macaques by ~55% from robust (12 intrarectal challenges) challenge with R5, tier 2 SHIV. In this study, the immune correlates of protection were NNAbs that mediated infected cell antibody binding, ADCC, ADCP of challenge SHIV and MIP1? expression by NK cells. The overall hypothesis of project 1 is that the efficacy of RV144 and the current HVTN 702 efficacy trial will be improved upon by use of mRNAs encoding trivalent ADCC mosaic Envs that are specifically designed to overcome NNAb epitope diversity. This will be accomplished by the following Specific Aims: Specific Aim 1. Design and produce multivalent nucleoside-modified mRNAs encoding either polyvalent WT or ADCC mosaic Env gp120s. Specific Aim 2. Determine the induction of NNAbs induced by trivalent ADCC mosaic vs. WT Envs in bnAb VH + VL UCA knock-in (KI) mice that express the RV144-derived V2 ADCC-mediating antibody, CH58. Specific Aim 3. Test ALVAC-C/trivalent ADCC Env gp120s in rhesus macaques (RMs) for ability to protect against an R5, tier 2 transmitted/founder SHIV for use in a phase I clinical trial in year 5.